The benzimidazoles are potent antitumour, antifungal and antiparasitic agents, whose mode of action is thought to result from their inhibition of microtubule formations (Goker, H.; Kus, C.; Boykin, D. W.; Yildiz, S.; Altanlar, N. Bioorg. Med. Chem. 2002, 10, 2859.; Seth, P. P.; Jefferson, E. A.; Risen, L. M.; Osgood, S. A. Bioorg. Med. Chem. Lett. 2003, 13, 1669.; Nare, B.; Liu, Z.; Prichard, R. K.; George, E. Biochem. Pharmacol. 1994, 48, 2215). Substituted benzimidazoles have proven as drug leads, which have exhibited pharmacological interest. A series of 2-phenyl benzimidazole-4-carboxamides have been synthesized and evaluated for in vitro and in vivo antitumour activity (Mahaimeed, H. A. Int. Med. Res. 1997, 25, 175.; Denny, W. A.; Rewcastle, G. W.; Baguly, B. C. J. Med. Chem. 1990, 33, 814). One of the bisbenzimidazole (Hoechst-33258) is known for the inhibition of DNA topoisomerase I with affinity to AT-rich sequences in DNA (Chen, A. Y.; Yu, C.; Bodley, A.; Peng, L. F.; Liu, L. F. Cancer Res. 1993, 53, 1332.; Alper, S.; Arpaci, O. T. E. S.; Aid, E.; Yalc, I. II Farmaco 2003, 58, 497.; Czarny, A.; Boykin, D. W.; Wood, A. A.; Nunn, C. M.; Neidle, S.; Zhao, M.; Wilson, W. D. J. Am. Chem. Soc. 1995, 117, 4716; Embrey, K. J.; Searle, M. S.; Craik, D. J. J. Chem. Soc. Chem. Commun. 1991, 1770; Fede, A.; Billeter, M.; Leupin, W.; Thrich, K. W. Structure 1993, 1, 177; 42.; Haq, I.; Ladbury, J. E.; Chowdhry, B. Z.; Jenkins, T. C.; Chaires, J. B. J. Mol. Biol. 1997, 271, 244). Based on such interesting results, a variety of bisbenzimidazole derivatives have been designed and synthesized. This addition of a benzimidazole unit in these dimers significantly enhanced the interaction with DNA to raise the ΔTm value to more than 20° C. Further the DNA footprinting experiments have shown that five to six base pairs are protected by trisbenzimidazole derivatives and possess potential of this class of compounds for the development of anticancer agents with DNA sequence recognition (Hua, J. Y.; Bur, D.; Hasler, W.; Schmitt, V. R.; Dorn, A.; Bailly, C.; Waring, M. J.; Hochstrassera, R.; Leupina, W. Bioorg. Med. Chem. 2001, 9, 2905).
Napthalimides are another interesting pharmacophores in the design of mono as well as bisintercalaters with good antitumour activity, some of these compounds like amonafide and mitonafide bind to double stranded DNA by intercalation and underwent clinical studies (Brana, M. F.; Ramos, A. Curr. Med. Chem. Anticancer Agents 2001, 1, 237.; Malviya, P. V. K.; Liu, Y.; Alberts, D. S.; Surwit, E. A.; Craig, J. B.; Hanningan, E. V. Am. J. Clin. Oncol. 1992, 15, 41.; Bousquet, P. F.; Brana, M. F.; Conlon, D.; Fitzgerald, K. M.; Perron, D.; Cocchiaro, C.; Miller, R.; Moran, M.; George, J.; Qian, X. D.; Keilhauer, G.; Romerdahl, C. Cancer Res. 1995, 55, 1176). Bisintercalation obtained by dimerization of these napthalimides exhibit much higher activity than the monomeric compounds and one such example is elinafide, which shows potent cellular cytotoxicity with excellent in vivo antitumour activity (Bailly, C.; Brana, M. F.; Waring, M. J. Eur. J. Biochem. 1996, 240, 195.; Brana, M. F.; Castellano, J. M.; Mora, M.; Vega, M. J. P; Romerdahl, C. R.; Qian, X. D.; Bousquet, P.; Emling, F.; Schlick, E.; Keilhauer, G. Anticancer Drug Des. 1993, 8, 257.; Brana, M. F.; Castellano, J. M.; Mora, M.; Vega, M. J. P; Perron, D.; Conlon, D.; Bousquet, P. F.; Romerdahl, C. A.; Robinson, S. P. Anticancer Drug Des. 1996, 11, 297; Thompson, J.; Pratt, C. B.; Stewart, C. F.; Bowman, L.; Zamboni, W. C.; Pappo, A. InVest. New Drugs 1998, 16, 45). Detailed molecular biology experiments have indicated that these bisnapthalimides intercalate DNA helix through the major groove (Bailly, C.; Brana, M. F.; Waring, J. Eur. J. Biochem. 1996, 240, 1955; (b) Gallego, J.; Reid, B. R. Biochemistry 1999, 38, 15104) and hence such a pharmacophore is important in the design of new chemical entities with anticancer activity.
This is in continuation to our earlier efforts towards the synthesis of new class of pyrrolobenzodiazepine (PBD) hybrids, which have the ability to recognize and subsequently form covalent bonds to specific base sequences of double stranded DNA (Thurston, D. E. In Molecular Aspects of Anticancer Drug—DNA Interactions.; Neidle, S.; Waring, M. J.; Eds.; Macmillan. London 1993, 1, 54.; Thurston, D. E. Br. J. Cancer 1999, 80, 65.; Thurston, D. E.; Morris, S. J.; Hartley, J. A. Chem. Commun. 1996, 563; Wilson, S. C.; Howard, P. W.; Forrow, S. M.; Hartley, J. A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. J. Med. Chem. 1999, 42, 4028), we have recently prepared PBD-napthalimide and PBD-benzimidazole conjugates. These have exhibited DNA binding ability and remarkable anticancer activity (Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K.; Ramesh, G. Bioorg. Med. Chem. Lett. 2002, 12, 1933.; Kamal, A.; Srinivas, O.; Ramulu, P.; Kumar, P, P. Bioorg. Med. Chem. Lett. 2003, 13, 3577.; Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G.; Kumar, P. P. Bioorg. Med. Chem. Lett. 2004, 12, 4337). This concept of mixed hybrids for dual action has been further taken forward in the present study wherein napthalimide moiety has been linked to the benzimidazole scaffold by suitable linker spacers. In this investigation two type of linker spacers have been utilized, that is one without piperazine moiety while the other with a piperazine moiety to improve the lipophilicity and also to understand the structure activity relationship aspects.